ArticleBiochemistry2017
Taking a Bite Out of Amyloid: Mechanistic Insights into α-Synuclein Degradation by Cathepsin L.
Article in Biochemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 32 citations in OpenAlex.
- Recombinant cathepsins B and L promote α-synuclein clearance and restore lysosomal function in human and murine models with α-synuclein pathology.Molecular neurodegeneration · 2025Article
- Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation.Nature communications · 2025Article
- Cellular processing of α-synuclein fibrils results in distinct physiological C-terminal truncations with a major cleavage site at residue Glu 114.The Journal of biological chemistry · 2023Article
- Reciprocal effects of alpha-synuclein aggregation and lysosomal homeostasis in synucleinopathy models.Translational neurodegeneration · 2023Article
- Cathepsin L-containing exosomes from α-synuclein-activated microglia induce neurotoxicity through the P2X7 receptor.NPJ Parkinson's disease · 2022Article
- The Role of Extracellular Matrix Components in the Spreading of Pathological Protein Aggregates.Frontiers in cellular neuroscience · 2022Review
- Targeted proteolytic products of τ and α-synuclein in neurodegeneration.Essays in biochemistry · 2021Article
- Article
- Cathepsin K is a potent disaggregase of α-synuclein fibrils.Biochemical and biophysical research communications · 2020Article
- The emerging role of α-synuclein truncation in aggregation and disease.The Journal of biological chemistry · 2020Review
- Glucocerebrosidase as a therapeutic target for Parkinson's disease.Expert opinion on therapeutic targets · 2020Review
- Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms.Frontiers in cell and developmental biology · 2020Review
- pH-Dependent fibril maturation of a Pmel17 repeat domain isoform revealed by tryptophan fluorescence.Biochimica et biophysica acta. Proteins and proteomics · 2019Article
- Structural Insights into α-Synuclein Fibril Polymorphism: Effects of Parkinson's Disease-Related C-Terminal Truncations.Journal of molecular biology · 2019Article
- C-terminal α-synuclein truncations are linked to cysteine cathepsin activity in Parkinson's disease.The Journal of biological chemistry · 2019Article
- Interplay between α-synuclein amyloid formation and membrane structure.Biochimica et biophysica acta. Proteins and proteomics · 2019Review
- Stimulation of α-synuclein amyloid formation by phosphatidylglycerol micellar tubules.Biochimica et biophysica acta. Biomembranes · 2018Article
- Effects of phosphatidylcholine membrane fluidity on the conformation and aggregation of N-terminally acetylated α-synuclein.The Journal of biological chemistry · 2018Article
- Structural features of α-synuclein amyloid fibrils revealed by Raman spectroscopy.The Journal of biological chemistry · 2018Article
- Fluorescence spectroscopy reveals N-terminal order in fibrillar forms of α-synuclein.Chemical communications (Cambridge, England) · 2018Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
A common hallmark of amyloids is their resistance to an array of proteases, highlighting the difficulty in degrading these disease-related aggregated proteinaceous materials. Here, we report on the potent activity of cathepsin L (CtsL), a lysosomal protease that proteolyzes the Parkinson's disease-related amyloid formed by α-synuclein (α-syn). Using liquid chromatography with mass spectrometry and transmission electron microscopy, an elegant mechanism is revealed on the residue and ultrastructural level, respectively. Specifically, CtsL always truncates α-syn fibrils first at the C-terminus before attacking the internal β-sheet-rich region between residues 30 and 100. This suggests that only upon removal of the α-syn C-terminus can CtsL gain access to residues within the amyloid core. Interestingly, three of the four mapped sites contain a glycine residue (G36, G41, and G51) that is likely to be involved in a β-turn in the fibril, whereupon cutting would lead to solvent exposure of internal residues and allow further proteolysis. Via close inspection of the fibril morphology, products resulting from CtsL degradation show imperfections along the fibril axis, with missing protein density as though they have been cannibalized. The ability of CtsL to degrade α-syn amyloid fibrils offers a promising strategy for improving the cellular clearance of aggregated α-syn through the modulation of protease levels and activity.
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